Compounds which are inhibitors of human immunodeficiency virus (HIV) protease are useful for inhibiting HIV protease in vitro and in vivo and are useful for inhibiting an HIV infection. Certain HIV protease inhibitors comprise a moiety which is a substituted 2,5-diamino-3-hydroxyhexane. HIV protease inhibitors of particular interest are compounds having formula 1: ##STR6## wherein A is R.sub.2 NHCH(R.sub.1)C(O)-- and B is R.sub.2a or wherein A is R.sub.2a and B is R.sub.2 NHCH(R.sub.1)C(O)-- wherein R.sub.1 is lower alkyl and R.sub.2 and R.sub.2a are independently selected from --C(O)--R.sub.3 --R.sub.4 wherein at each occurrence R.sub.3 is independently selected from O, S and --N(R.sub.5)-- wherein R.sub.5 is hydrogen or lower alkyl and at each occurrence R.sub.4 is independently selected from heterocyclic or (heterocyclic)alkyl; or a pharmaceutically acceptable salt, prodrug or ester thereof. Compounds of formula 1 are disclosed in U.S. Pat. No. 5,354,866, issued Oct. 11, 1994, U.S. Pat. No. 5,541,206, issued Jul. 30, 1996, and U.S. Pat. No. 5,491,253, issued Feb. 13, 1996.
A preferred HIV protease inhibitor having formula 1 is a compound of formula 2a: ##STR7## or a pharmaceutically acceptable salt, prodrug or ester thereof.
Another preferred HIV protease inhibitor of formula 1 is a compound of formula 2b: ##STR8## The compound having formula 2b is disclosed in U.S. Pat. No. 5,421,206, issued Jul. 30, 1996.
An intermediate which is especially useful for preparing compounds having formula 1 and 2 is a substantially pure compound having the formula 3: ##STR9## wherein R.sub.6, R.sub.7 and R.sub.8 are independently selected from hydrogen and N-protecting groups, such as, for example, t-butyloxycarbonyl (Boc), benzyl and the like; or an acid addition salt thereof. The preparation of compounds having formula 3 has been disclosed in U.S. Pat. No. 5,491,253, issued Feb. 13, 1996 (the '253 patent).
The procedure disclosed in the '253 patent starts with a protected L-phenylalanine benzyl ester. The ester is reacted with an (.alpha.-carbanion of acetonitrile in an inert solvent to provide a ketonitrile, shown below. ##STR10## Reaction of the ketonitrile with a benzyl Grignard, usually more than about 3 equivalents, provides the enamine product. The enamine can be readily transformed into compound 3.
An object of the present invention is to provide a simple method for the preparation of enamines which can be converted into diaminols having formula 3.
An object of the present invention is to provide a method for the preparation of enamines which provides the enamines in high yield.